Tirzepatide improves extracellular matrix integrity and vascularization in pancreatic islets of a mouse model of obesity, diabetes, and menopause.

Tirzepatide, a dual GIP/GLP-1 receptor agonist, appears to protect pancreatic islet structures under metabolic stress. This study examined its effects on extracellular matrix organization in female mice exposed to obesity, diabetes, and menopause, compared to control and untreated groups. Tirzepatide significantly decreased the expression of collagen types I and VI, matrix metalloproteinases 2 and 9, and the hyaluronan receptor CD44, while restoring levels of perlecan and heparan sulfate proteoglycans. These molecular changes were associated with increased vascular endothelial growth factor expression, improved endothelial labeling, and maintained capillary organization within the islets. Tirzepatide also reduced transcripts related to amyloid formation and enzymes responsible for extracellular matrix breakdown, indicating decreased fibrosis and cytotoxic remodeling. Multivariate analysis identified tirzepatide as the primary factor affecting extracellular matrix modulation. Overall, tirzepatide countered fibrosis, inflammation, and amyloid stress, preserving pancreatic islet structure and supporting its potential to protect islet function in metabolic and hormonal disorders.